Abstract

The formation of cellular spheroid aggregates in the Intraperitoneal Cavity (IP) is considered to be an important step in the metastatic progression of ovarian cancer. Spheroids may represent a unique morphological adaptation that enhances long-term survival of tumor cells in the IP cavity, reminiscent of dormant cell populations. Like other dormant tumor cells, in vivo-isolated and in vitro-cultured spheroids exhibit enhanced chemoresistance and display markers of quiescence. We show that expression of mitochondrial superoxide dismutase (Sod2), which regulates mitochondrial redox balance, is significantly increased during formation of dense spheroids from a number of ovarian cancer cell lines. This is accompanied by increases in the quiescence marker p27(kip1). Importantly, siRNA and shRNA knock-down of Sod2 compromise spheroid formation and integrity, and abrogate increases in p27(kip1) expression in anchorage-independent 3D cultures. Mechanistically, it is likely that increases in Sod2 expression protect cells from build-up of mitochondrial and IP cavity-derived ROS, enhancing their survival as dormant spheroid populations. In addition, bioenergetic data suggest that Sod2 is directly involved in enhancing the mitochondrial integrity of tumor cells within spheroid aggregates. This leads to a metabolic profile that is associated with a slowing in ATP demand and an enhanced respiratory reserve capacity, with Sod2 being intricately involved in manipulating these changes. Enhanced Sod2 expression, a concomitant decrease in mitochondrial ROS and changes in mitochondrial function are likely indicators of a quiescence adaptation of tumor spheroids, necessary for survival in the IP cavity. Manipulating mitochondrial function and redox balance by effectively targeting mitochondrial antioxidant enzymes may provide novel therapeutic strategies to combat recurrence and metastatic spread of ovarian cancer.